Clinical Indicators of Fatal Dengue in Two Endemic Areas of Colombia: A Hospital-Based Case-Control Study.

According to the World Health Organization, 98% of fatal dengue cases can be prevented; however, endemic countries such as Colombia have recorded higher case fatality rates during recent epidemics. We aimed to identify the predictors of mortality that allow risk stratification and timely intervention in patients with dengue. We conducted a hospital-based, case-control (1:2) study in two endemic areas of Colombia (2009-2015). Fatal cases were defined as having either 1) positive serological test (IgM or NS1), 2) positive virological test (RT-PCR or viral isolation), or 3) autopsy findings compatible with death from dengue. Controls (matched by state and year) were hospitalized nonfatal patients and had a positive serological or virological dengue test. Exposure data were extracted from medical records by trained staff. We used conditional logistic regression (adjusting for age, gender, disease's duration, and health-care provider) in the context of multiple imputation to estimate exposure to case-control associations. We evaluated 110 cases and 217 controls (mean age: 35.0 versus 18.9; disease's duration pre-admission: 4.9 versus 5.0 days). In multivariable analysis, retro-ocular pain (odds ratios [OR] = 0.23), nausea (OR = 0.29), and diarrhea (OR = 0.19) were less prevalent among fatal than nonfatal cases, whereas increased age (OR = 2.46 per 10 years), respiratory distress (OR = 16.3), impaired consciousness (OR = 15.9), jaundice (OR = 32.2), and increased heart rate (OR = 2.01 per 10 beats per minute) increased the likelihood of death (AUC: 0.97, 95% confidence interval: 0.96, 0.99). These results provide evidence that features of severe dengue are associated with higher mortality, which strengthens the recommendations related to triaging patients in dengue-endemic areas.

Regulators of endothelial integrity as severity predictors in dengue.

INTRODUCTION: Dengue is currently among the mosquito-borne diseases of greatest global impact. The clinical course of the disease can be unpredictable, so proper handling in its early stages is critical to ensure optimal outcomes.  OBJECTIVE: To evaluate serum regulators of endothelial integrity (VEGF, sICAM-1, sEndoglina, Ang-1, and Ang-2) as predictive markers of dengue severity.  MATERIALS AND METHODS: We conducted a case-control study nested in an appropriate cohort. Endothelial regulator levels were first measured by ELISA, after which analysis was performed using logistic regression of clinical and regulatory variables, with severity as an output variable. A possible severity prediction model, based on the variables of interest and output, was defined using the best area under the ROC curve.  RESULTS: The median subject age was 24 years. Severe cases were associated with Ang-2 serum levels of ≥1,490 ng/ml (OR=3.1; p=0.015). Serum levels of Ang-2 (≥1,490 ng/ml) contributed to the severity prediction model, as did a 0.73 area under the ROC curve, together with the variables rash, impaired consciousness and abdominal pain, with an OR of 3.2 (CI 95%: 1.16 to 8.9; p=0.024).  CONCLUSION: The endothelial regulator Ang-2 could be a predictor of severity in dengue.

Reguladores de integridad endotelial como posibles predictores de la gravedad en casos de dengue / Regulators of endothelial integrity as severity predictors in dengue

Introducción. El dengue es una de las enfermedades trasmitidas por mosquitos de mayor impacto en el mundo. La evolución clínica de la enfermedad suele ser impredecible, por lo cual su adecuado manejo en las fases tempranas podría incidir en la mejoría del paciente. Objetivo. Evaluar los niveles séricos de algunos reguladores endoteliales (VEGF, sICAM-1, endoglina soluble, Ang-1 y Ang-2) como marcadores de predicción de la gravedad del dengue. Materiales y métodos. Se hizo un estudio de casos y controles anidado en una cohorte. En la fase temprana, los niveles de los reguladores endoteliales se midieron con ELISA. La relación entre las variables clínicas y los reguladores se analizó mediante regresión logística utilizando como variable de salida la gravedad del dengue. Con base en la relación entre las variables de interés y el resultado, se estableció un posible modelo predictor de la gravedad empleando la mejor área bajo la curva (ROC). Resultados. La mediana de la edad fue de 24 años. Los casos graves se asociaron con niveles séricos de Ang-2 a partir de un punto de corte mayor o igual a 1.490 pg/ml, ( Odds ratio, OR=3,1 p=0,015). Los niveles séricos de Ang-2, así como un área de 0,73 bajo la curva ROC, contribuyeron al modelo de predicción de la gravedad, conjuntamente con las variables de exantema, trastorno de conciencia y dolor abdominal, con OR de 3,2 (IC 95% 1,16-8,9; p=0,024). Conclusión. El regulador endotelial Ang-2 podría ser un predictor de la gravedad en el dengue.

Introduction: Dengue is currently among the mosquito-borne diseases of greatest global impact. The clinical course of the disease can be unpredictable, so proper handling in its early stages is critical to ensure optimal outcomes. Objective: To evaluate serum regulators of endothelial integrity (VEGF, sICAM-1, sEndoglina, Ang-1, and Ang-2) as predictive markers of dengue severity. Materials and methods: We conducted a case-control study nested in an appropriate cohort. Endothelial regulator levels were first measured by ELISA, after which analysis was performed using logistic regression of clinical and regulatory variables, with severity as an output variable. A possible severity prediction model, based on the variables of interest and output, was defined using the best area under the ROC curve. Results: The median subject age was 24 years. Severe cases were associated with Ang-2 serum levels of =1,490 ng/ml (OR=3.1; p=0.015). Serum levels of Ang-2 (=1,490 ng/ml) contributed to the severity prediction model, as did a 0.73 area under the ROC curve, together with the variables rash, impaired consciousness and abdominal pain, with an OR of 3.2 (CI 95%: 1.16 to 8.9; p=0.024). Conclusion: The endothelial regulator Ang-2 could be a predictor of severity in dengue.

Host biomarkers are associated with progression to dengue haemorrhagic fever: a nested case-control study.

OBJECTIVES: Dengue represents the most important arboviral infection worldwide. Onset of circulatory collapse can be unpredictable. Biomarkers that can identify individuals at risk of plasma leakage may facilitate better triage and clinical management. DESIGN: Using a nested case-control design, we randomly selected subjects from a prospective cohort study of dengue in Colombia (n=1582). Using serum collected within 96 hours of fever onset, we tested 19 biomarkers by ELISA in cases (developed dengue hemorrhagic fever or dengue shock syndrome (DHF/DSS); n=46), and controls (uncomplicated dengue fever (DF); n=65) and healthy controls (HC); n=15. RESULTS: Ang-1 levels were lower and angptl3, sKDR, sEng, sICAM-1, CRP, CXCL10/IP-10, IL-18 binding protein, CHI3L1, C5a and Factor D levels were increased in dengue compared to HC. sICAM-1, sEng and CXCL10/IP-10 were further elevated in subjects who subsequently developed DHF/DSS (p=0.008, p=0.028 and p=0.025, respectively). In a logistic regression model, age (odds ratio (OR) (95% CI): 0.95 (0.92-0.98), p=0.001), hyperesthesia/hyperalgesia (OR; 3.8 (1.4-10.4), p=0.008) and elevated sICAM-1 (>298ng/mL: OR; 6.3 (1.5-25.7), p=0.011) at presentation were independently associated with progression to DHF/DSS. CONCLUSIONS: These results suggest that inflammation and endothelial activation are important pathways in the pathogenesis of dengue and sICAM-1 levels may identify individuals at risk of plasma leakage.

Host biomarkers distinguish dengue from leptospirosis in Colombia: a case-control study.

BACKGROUND: Dengue fever and leptospirosis have partially overlapping geographic distributions, similar clinical presentations and potentially life-threatening complications but require different treatments. Distinguishing between these cosmopolitan emerging pathogens represents a diagnostic dilemma of global importance. We hypothesized that perturbations in host biomarkers can differentiate between individuals with dengue fever and leptospirosis during the acute phase of illness. METHODS: We randomly selected subjects from a prospective cohort study of acute febrile illness in Bucaramanga, Colombia and tested 19 serum biomarkers by ELISA in dengue fever (DF, n = 113) compared to subjects with leptospirosis (n = 47). Biomarkers were selected for further analysis if they had good discriminatory ability (area under the ROC curve (AUC) >0.80) and were beyond a reference range (assessed using local healthy controls). RESULTS: Nine biomarkers differed significantly between dengue fever and leptospirosis, with higher levels of Angptl3, IL-18BP, IP-10/CXCL10, Platelet Factor 4, sICAM-1, Factor D, sEng and sKDR in dengue and higher levels of sTie-2 in leptospirosis (p < 0.001 for all comparisons). Two biomarkers, sEng and IL18BP, showed excellent discriminatory ability (AUROC >0.90). When incorporated into multivariable models, sEng and IL18BP improved the diagnostic accuracy of clinical information alone. CONCLUSIONS: These results suggest that host biomarkers may have utility in differentiating between dengue and leptospirosis, clinically similar conditions of different etiology.